This is an application for a Multi-Institutional Collaborative Research Project (MICRP) to conduct a genome search for genetic loci linked to the autism phenotype. This MICRP involves the collaboration of two independent sites: Tufts-New England Medical Center (PI:Susan Folstein) and The University of Iowa (PI: Joseph Piven). The PI's at these two sites have collaborated extensively over the past 8 years in genetic epidemiologic studies of autism. Preliminary data presented in this proposal replicate and expand on previous work by the PI's suggesting that a broader autism phenotype, which includes behavioral characteristics that are qualitatively similar to the defining features of autism, is genetically- related to autistic disorder. To maximize the likelihood of finding a significant linkage over a number of plausible genetic models we propose to employ both narrow and broad definitions of the autism phenotype. Specifically we plan to: 1) conduct a sib pair study of 150 autistic sib pairs; 2) conduct a linkage study of the broader, autism phenotype using 150 nuclear families ascertained through two autistic siblings; and, 3) conduct a linkage study of the broader autism phenotype using 50 moderate sized pedigrees ascertained through both autistic sib pairs and other (e.g., first cousin pairs) autistic relative pairs. Preliminary power analyses suggest excellent power to detect linkage under several possible models. The full collaboration of three data collection sites (Tufts, Iowa, Johns Hopkins) and two laboratory and data analytic sites (Tufts/Harvard and Iowa) will facilitate rapid data collection, genotyping and analysis, as well as provide sample sizes sufficient for an internal replication under some models. As a result of previous and ongoing studies by the PI's in Baltimore and Iowa an additional sample of 100 autistic probands, well characterized by standardized measures, is available for follow-up of significant findings of linkage by testing for allelic association and applicability of the findings to the general population.
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